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Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans

McLaren, P.J., Ripke, S., Pelak, K., Weintrob, A.C., Patsopoulos, N.A., Jia, X., Erlich, R.L., Lennon, N.J., Kadie, C.M., Heckerman, D., Gupta, N., Haas, D.W., Deeks, S.G., Pereyra, F., Walker, B.D., de Bakker, P.I.W. and John, M. (2012) Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans. Human Molecular Genetics, 21 (19). pp. 4334-4347.

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A small proportion of human immunodeficiency virus-1 (HIV-1) infected individuals, termed HIV-1 controllers, suppress viral replication to very low levels in the absence of therapy. Genetic investigations of this phenotype have strongly implicated variation in the class I major histocompatibility complex (MHC) region as key to HIV-1 control. We collected sequence-based classical class I HLA genotypes at 4-digit resolution in HIV-1-infected African American controllers and progressors (n = 1107), and tested them for association with host control using genome-wide single nucleotide polymorphism data to account for population structure. Several classical alleles at HLA-B were associated with host control, including B*57:03 [odds ratio (OR) = 5.1; P= 3.4 × 10(-18)] and B*81:01 (OR = 4.8; P= 1.3 × 10(-9)). Analysis of variable amino acid positions demonstrates that HLA-B position 97 is the most significant association with host control in African Americans (omnibus P = 1.2 × 10(-21)) and explains the signal of several HLA-B alleles, including B*57:03. Within HLA-B, we also identified independent effects at position 116 (omnibus P= 2.8 × 10(-15)) in the canonical F pocket, position 63 in the B pocket (P= 1.5 × 10(-3)) and the non-pocket position 245 (P= 8.8 × 10(-10)), which is thought to influence CD8-binding kinetics. Adjusting for these HLA-B effects, there is evidence for residual association in the MHC region. These results underscore the key role of HLA-B in affecting HIV-1 replication, likely through the molecular interaction between HLA-B and viral peptides presented by infected cells, and suggest that sites outside the peptide-binding pocket also influence HIV-1 control.

Item Type: Journal Article
Publisher: Oxford University Press
Copyright: © 2012 The Author.
Other Information: Mina John appears courtesy of the International HIV controllers study group
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